TY - JOUR T1 - PHYSIOLOGICAL DISPOSITION AND BIOTRANSFORMATION OF <em>LEVO</em>-METHADONE-1-<sup>3</sup>H IN THE DOG JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 34 LP - 44 VL - 188 IS - 1 AU - A. L. Misra AU - R. Bloch AU - N. L. Vadlamani AU - S. J. Mulé Y1 - 1974/01/01 UR - http://jpet.aspetjournals.org/content/188/1/34.abstract N2 - A method with minimal sensitivity of 1 to 2 ng, previously developed for levo-methadone after small doses has been used to estimate this drug in selected anatomical areas of the central nervous system and the peripheral tissues of the dog. After a 2 mg/kg (free base) s.c. dose of levo-methadone-1-3H to the dog, peak levels of drug in plasma (143 ng/ml) and in different anatomical areas of the central nervous system (1270-2029 ng/g) occurred at two hours. Measurable quantities of drug persisted in different areas of the dog brain and peripheral tissues for at least three weeks. At the same time the concentrations in plasma were barely detectable at periods of one and three weeks after drug administration. High levels of methadone were observed in lung, liver, spleen, kidney, heart and intestine with somewhat lower concentrations in muscle and fat. The approximate half-life of levo-methadone in dog plasma after a 2 mg/kg s.c. dose was six to seven hours and that in temporal cortex, hypothalamus, cerebellum and caudate nucleus ranged between three and four hours. The mean percentages of free drug excreted in the urine and feces of dogs 96 hours after a single 2 mg/kg s.c. dose were 19.4%, conjugated acid-hydrolyzable metabolites, 5.4% and total radioactivity, 68.3%. The values of conjugated metabolites and total radioactivity in dogs given chronic injections of methadone were significantly lower than those in acute animals. levo-Methadone was extensively metabolized by: 1) N-dealkylation and cyclization to substituted pyrrolidine and pyrroline metabolites; 2) N-oxidation; 3) hydroxylation in the para position of the aromatic nucleus; 4) keto group reduction; 5) glucuronide conjugation of resultant hydroxyl groups; and 6) minor conversion to secondary and primary amines. Persistence of levo-methadone and a metabolite in selected anatomical areas of the central nervous system of the dog and the binding of the metabolite to a specific brain protein could conceivably lead to a biochemical alteration of the receptor site and result in a reduced ability of the drug to initiate a pharmacological response. Possible relevance of these observations to the phenomena of pharmacological tolerance and the protracted course of the withdrawal syndrome observed with methadone are described. © 1974 by The Williams &amp; Wilkins Company ER -